Intermolecular Gold(I)‐Catalyzed Alkyne Carboalkoxylation Reactions for the Multicomponent Assembly of β‐Alkoxy Ketones

Abstract

Supporting InformationExperimental procedures and characterization data for new compounds in Tables 1-2 and Equations 1-5. Table of Contents General Considerations S1Preparation and Characterization of Products S1 Assignment of Stereochemistry of 26 and 27 S9 References S9Copies of 1 H and 13 C NMR Spectra S10 General: All reactions were carried out at room temperature in sealed tubes under a nitrogen atmosphere. All (NHC)AuNTf 2 and (phosphine)AuNTf 2 catalysts were prepared according to procedures reported by Gagosz. [1] All aldehydes, alcohols and alkynes used in Tables 1-2 and Equation 1 were purchased from commercial sources (Sigma-Aldrich Chemical Co. or Acros Chemical Co.) and used without further purification. Compounds 29 and 31 in Equations 3-4 were purchased from Sigma-Aldrich Chemical Co. and used without further purification.Dichloromethane was purified using a GlassContour solvent purification system. Structural and stereochemical assignments were made on the basis of 2-D COSY, HSQC, and NOESY experiments. Ratios of diastereomers were determined by 1 H NMR analysis. Yields refer to isolated yields of compounds estimated to be ≥95% pure as determined by 1 H NMR analysis unless otherwise noted. Synthesis and Characterization of β-Alkoxy Ketone Products S2General procedure: Au(I)-catalyzed synthesis of β-alkoxy ketones. An oven-dried test tube was equipped with a magnetic stir bar and cooled under a stream of N 2 before being charged with SPhosAuNTf 2 (5 mol%). The tube was then charged with a 0.1 M CH 2 Cl 2 solution of aldehyde (1 equiv), alkyne (1.5 equiv) and alcohol (3 equiv) before being sealed with a septum.The resulting mixture was stirred at room temperature and monitored by TLC analysis. After the starting material was consumed, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel using hexanes/ethyl acetate as the eluent. 3-(4-Bromophenyl)-3-methoxy-1-phenylpropan-1-one (10).The reaction of 2chlorobenzaldehyde (65 mg, 0.35 mmol) with phenylacetylene (59 µl, 0.53 mmol) and methanol (43 µl, 1.05 mmol) was conducted according to the general procedure. This procedure afforded 65 mg (59%) of the title compound as a pale yellow oil. 1

Gold-catalyzed multicomponent reactions

“…In 2012, Wolfe and co-workers developed a new Au( i )-catalyzed MCRs of alkyne 6a , aldehyde 6b , and alcohol 6c to generate β-alkoxy ketone 6d (Scheme 6). 32 The reaction was proposed to proceed through the hydration of alkyne 6a in the presence of gold( i ) species to produce 6e . Simultaneously, aldehyde 6b could react with alcohol 6c in the presence of the Au( i ) catalyst to generate acetal 6f , which then combines with the so-formed ketone 6e to form oxocarbenium intermediate 6g .…”

Gold Catalyzed Multicomponent Reactions beyond A3 Coupling

“…In this field, a gold(I)-catalyzed multicomponent synthesis of β-alkoxyketones from readily available precursors such as aldehydes 23 , alcohols 25 , and alkynes 24 was described in 2012 by Schultz and co-workers. The authors used the gold complex SPhosAuNTf 2 as a catalyst to prepare diverse β-alkoxyketone products 26 ( Scheme 10 ) [ 73 ].…”

Silver and gold-catalyzed multicomponent reactions

“…Finally, Wolfe and co-workers recently described a nice Au(I)-catalyzed MCR of readily available aldehydes, alcohols and alkynes for the synthesis of β-alkoxy ketones 108 [ 111 ]. The initial steps of the MCR encompass the Au(I)-catalyzed hydration of the alkyne to give the ketone 105 and the conversion of the aldehyde to the corresponding acetal 106 .…”